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Abstract:

The present invention relates to pharmaceutical compositions comprising
tramadol and celecoxib and their uses as medicaments or analgesics, more
particularly for the treatment of severe to moderate pain with an
inflammation component.

Claims:

1. A pharmaceutical composition comprising a combination of
(rac)-tramadol.HCl and celecoxib or a pharmaceutically acceptable salt or
hydrate thereof.

2. A pharmaceutical composition according to claim 1 wherein the
celecoxib is in neutral form.

3. A pharmaceutical composition according to claim 1 wherein the ratio of
the (rac)-tramadol.HCl to the celecoxib is a molar ratio of from about
1:1 to about 1:300 or from about 1:1 to about 300:1.

4. A pharmaceutical composition according to claim 1 wherein the
molecular ratio of the (rac)-tramadol.HCl to the celecoxib is a molar
ratio of from about 1:1 to about 1:30 or from about 1:1 to about 30:1.

5. A pharmaceutical composition according to claim 1 wherein the
molecular ratio of the (rac)-tramadol.HCl to the celecoxib is a molar
ratio of from about 1:1 to about 1:5 or from about 1:1 to about 5:1.

6. A method for the treatment of pain comprising administering to a
subject in need thereof a therapeutically effective amount of at least
one pharmaceutical composition according to claim 1.

Description:

[0001] The present invention relates to pharmaceutical compositions
comprising tramadol and celecoxib and their uses as medicaments or
analgesics, more particularly for the treatment of severe to moderate
pain.

[0002] Pain is a complex response that has been functionally categorized
into sensory, autonomic, motor, and affective components. The sensory
aspect includes information about stimulus location and intensity while
the adaptive component may be considered to be the activation of
endogenous pain modulation and motor planning for escape responses. The
affective component appears to include evaluation of pain unpleasantness
and stimulus threat as well as negative emotions triggered by memory and
context of the painful stimulus.

[0003] In general, pain conditions can be divided into chronic and acute.
Chronic pain includes neuropathic pain and chronic inflammatory pain, for
example arthritis, or pain of unknown origin, as fibromyalgia. Acute pain
usually follows non-neural tissue injury, for example tissue damage from
surgery or inflammation, or migraine. Pain may also be divided into
different levels of severity starting from severe through moderate to
light pain.

[0004] There are many drugs that are known to be useful in the treatment
or management of pain. Opioids are frequently used as analgesics in pain.
Derivatives of morphine are indicated for the treatment of moderate to
acute pain in human. The analgesic effect is obtained through their
action on morphinic receptors, preferably the p-receptors. Among these
derivatives of morphine, morphine, codeine, pethidine,
dextropropoxyphenemethadone, lenefopan may be mentioned.

[0005] One of the morphinic derivatives that has shown very good results
when orally administrated, and which is extensively marketed, is
tramadol, also available as a physiologically acceptable salt,
particularly as a chlorohydrate. Tramadol is a central acting analgesic
drug that exerts its effects by activating opioid receptors and enhancing
neuronal monoamine synaptic concentration. Tramadol, whose chemical name
is 2-(dimethylaminomethyl)-1-(3-methoxyphenyl)cyclohexanol, has the
following formula:

##STR00001##

[0006] This structure shows two different chiral centers and thus the
molecule may exist in different diastereoisomers among which the tramadol
is the cis-diastereoisomer. The enantiomers (1R,2R), or (1S,2S), are also
known as (+)-tramadol and (-)-tramadol with both of them contributing in
different ways to the overall activity of racemic tramadol.

[0007] "(rac)" is according to this invention defined as the abbreviation
of "racemate" and thus "(rac)-tramadol" or "(rac)tramadol" means racemic
tramadol (the cis-diastereoisomer) as described in the paragraph above.

[0008] Accordingly, "(rac)-tramadol.HCl" or "(rac)tramadol.HCl" is defined
as the hydrochloride salt of racemic tramadol (the cis-diastereoisomer)
as described above.

[0009] From the art it appears that this compound is neither fully
opioid-like, nor non-opioid-like. Some studies have demonstrate that
tramadol is an opioid agonist, whereas clinical experience indicates that
it lacks many of the typical side effects of opioids agonist, for example
respiratory depression, constipation or tolerance.

[0010] Due to their drawbacks, opioids used as analgesics to treat pain
cannot always be given repeatedly or at higher doses. The effects of
opioids are reviewed for example by J. Jaffe in "Goodman and Gilman's,
The Pharmacological Basis of Therapeutics", 8th edition; Gilman et al.;
Pergamon Press, New York, 1990, Chapter 22, pages 522-573.

[0011] Consequently it has been proposed to combine opioids with other
drugs that are not opioid analgesic agents, in order to lower the amount
of opioids needed to produce an equivalent degree of analgesia. Among
these combinations, the association of tramadol with nonsteroidal
anti-inflammatory drugs (NSAIDs) has been reported to be of particular
interest (EP-0 546 676).

[0012] U.S. Pat. No. 5,516,803 discloses combination of tramadol with
non-steroidal anti-inflammatory drugs (NSAIDs), specifically ibuprofen
and discloses the combination of tramadol.HCl with non-steroidal
anti-inflammatories, such as for example ibuprofen, in a composition
ratio of 1:1 to 1:200 producing a synergistically enhanced analgesic
action and reducing the undesired accompanying symptoms

[0013] U.S. Pat. No. 6,558,701 patent discloses combination of tramadol
with diclofenac and "for the treatment of moderate to severe pain, the
World Health Organization (WHO) recommends combining opioid analgesics
with non-steroidal analgesics in order to produce a more effective pain
relief and possibly reduce amounts of analgesic which are necessary to
administer".

[0014] One interesting NSAIDs to be combined with tramadol is the marketed
drug celecoxib, whose chemical name is
4-[5-(4-methylphenyl)-3-(trifluoromethyl)-pyrazol-1-yl]-benzenesulfonamid-
e. Celecoxib is an anti-inflammatory and pain killer drug and it is one of
the most used treatments for chronic musculo-skeletal inflammatory
illnesses. It has an empirical formula of
C17H14F3N3O2S.

##STR00002##

[0015] Celecoxib is an oral, highly selective cyclooxygenase-2 (COX-2)
inhibitor, and it is indicated for the treatment of symptomatic relief in
the treatment of osteoarthritis, rheumatoid arthritis and ankylosing
spondylitis (Goldenberg MM. Celecoxib, a selective cyclooxygenase-2
inhibitor for the treatment of rheumatoid arthritis and osteoarthritis.
Clin. Ther. 1999, 21, 1497-513). This high selectivity allows celecoxib
and other COX-2 inhibitors to reduce inflammation (and pain) while
minimizing gastrointestinal adverse drug reactions (e.g. stomach ulcers)
that are common with non-selective NSAIDs.

[0016] Cyclooxygenase is responsible for generation of prostaglandins. Two
isoforms, COX-1 and COX-2, have been identified. COX-2 is the isoform of
the enzyme that has been shown to be induced by pro-inflammatory stimuli
and has been postulated to be primarily responsible for the synthesis of
prostanoid mediators of pain, inflammation, and fever. COX-2 is also
involved in ovulation, implantation and closure of the ductus arteriosus,
regulation of renal function, and central nervous system functions (fever
induction, pain perception and cognitive function). It may also play a
role in ulcer healing. COX-2 has been identified in tissue around gastric
ulcers in man but its relevance to ulcer healing has not been
established.

[0017] WO00/51685 describes pharmaceutical composition comprising on one
hand a tramadol material selected from: [0018] (+)- and (-)-tramadol,
racemic tramadol, the N-oxide of tramadol and O-desmethyl-tramadol (both
of them as isolated stereoisomers or mixtures thereof including their
racemates) either as free base or as a salt, solvate or polymorph; and on
the other hand a selective COX-2 inhibitor with celecoxib being listed
among the COX-2 inhibitor drugs. The focus of the application rests in
the exemplified combination of tramadol and JT-522.

[0019] The applicant has now found that tramadol, especially the
(rac)-tramadol hydrochloride salt, having the opioid activity, and
celecoxib (especially in its neutral form) can be combined in one
pharmaceutical composition achieving an additive effect, especially in
the treatment of severe to moderate pain, especially in pain with an
inflammatory element.

[0020] Thus the object of the present invention is a pharmaceutical
composition comprising a combination of (rac)tramadol.HCl and celecoxib
or a pharmaceutically acceptable salt or hydrate thereof.

[0021] In general each separate active principle of the pharmaceutical
composition according to the invention, the tramadol and the celecoxib,
has its own disadvantages when used alone.

[0022] Thus, tramadol hydrochloride, which is often used orally, displays
a highly bitter taste, which makes the drugs often difficult to swallow
and lowers patient compliance. Also, as stated before, the drawbacks
associated with opioids--their side effects--are limiting their use, so
that they have to be given at lower doses and often less frequent as
their use as analgesics to treat pain would normally require. On the
other hand celecoxib is well-known to be only slightly soluble in water
and this is further limiting its use in pharmaceutical formulations.

[0023] The object of the present invention is to provide a pharmaceutical
composition comprising an opioid like tramadol and an NSAID like
celecoxib having a level of efficacy similar to the one achievable by
each active substance used alone, but: [0024] with a better safety
profile at higher doses and/or [0025] --by showing a synergistic
effect--allowing a reduction of dose while still delivering the desired
activity using less of each ingredient and, therefore, reducing the side
effects associated with each active principle; and/or [0026] providing a
new more effective method for treating acute or severe to moderate pain,
especially in pain with an inflammatory component.

[0027] Other desirable improvements/advantages of the new pharmaceutical
composition would include being active in diseases or symptoms being or
related to pain and its subtypes, especially those in which current
treatment is insufficient like sciatica or frozen shoulder or pain
related to central sensitization (central pain syndrome).

[0028] Most desirably the pharmaceutical composition should combine more
than one, most preferably all of these advantages.

[0029] This pharmaceutical composition according to the invention shows
improved properties if compared to any of the active principles alone.

[0030] In one preferred embodiment of the pharmaceutical composition
according to the invention the celecoxib is in neutral form.

[0031] As celecoxib is weakly acidic with a pKa of 11.1 its "neutral form"
according to the invention is defined therefore as the form in which
celecoxib is free (not in form of a salt) but is--depending on the
pH--neutral or carrying a load.

[0032] In one further embodiment of the pharmaceutical composition
according to the invention the ratio of the (rac)-tramadol.HCl to the
celecoxib is a weight ratio of from about 1:1 to about 1:300 or from
about 1:1 to about 300:1.

[0033] In one further embodiment of the pharmaceutical composition
according to the invention the ratio of the (rac)-tramadol.HCl to the
celecoxib is a molar ratio of from about 1:1 to about 1:300 or from about
1:1 to about 300:1.

[0034] In one further embodiment of the pharmaceutical composition
according to the invention the molecular ratio of the (rac)-tramadol.HCl
to the celecoxib is a weight ratio of from about 1:1 to about 1:30 or
from about 1:1 to about 30:1.

[0035] In one further embodiment of the pharmaceutical composition
according to the invention the molecular ratio of the (rac)-tramadol.HCl
to the celecoxib is a molar ratio of from about 1:1 to about 1:30 or from
about 1:1 to about 30:1.

[0036] In one further embodiment of the pharmaceutical composition
according to the invention the molecular ratio of the (rac)-tramadol.HCl
to the celecoxib is a molar ratio of from about 1:1 to about 1:5 or from
about 1:1 to about 5:1.

[0037] Another advantage is that the association of the two active
principles into one unique species seems to allow for a better
Pharmacokinetic/Pharmacodynamic (PKPD) including also a better
penetration of the blood-brain barrier, which helps in the treatment of
pain.

[0038] Both parts of the pharmaceutical composition are well-known drugs
used for a long time worldwide. Due to the therapeutic interest in
tramadol in the treatment of pain symptoms and the well-known properties
of celecoxib in this field of medical indication, a further object of the
present invention is a medicament containing a pharmaceutical composition
comprising (rac)-tramadol.HCl and celecoxib.

[0039] Thus, the invention also relates to a medicament containing a
pharmaceutical composition comprising (rac)-tramadol.HCl and celecoxib
according to the invention as described above and optionally one or more
pharmaceutically acceptable excipients.

[0040] The medicament or pharmaceutical composition according to the
present invention may be in any form suitable for the application to
humans and/or animals, preferably humans including infants, children and
adults and can be produced by standard procedures known to those skilled
in the art. The medicament can be produced by standard procedures known
to those skilled in the art, e.g. from the table of contents of
"Pharmaceutics: The Science of Dosage Forms", Second Edition, Aulton, M.
E. (ED. Churchill Livingstone, Edinburgh (2002); "Encyclopedia of
Pharmaceutical Technology", Second Edition, Swarbrick, J. and Boylan J.
C. (Eds.), Marcel Dekker, Inc. New York (2002); "Modern Pharmaceutics",
Fourth Edition, Banker G. S. and Rhodes C. T. (Eds.) Marcel Dekker, Inc.
New York 2002 y "The Theory and Practice of Industrial Pharmacy", Lachman
L., Lieberman H. And Kanig J. (Eds.), Lea & Febiger, Philadelphia (1986).
The respective descriptions are hereby incorporated by reference and form
part of the disclosure. The composition of the medicament may vary
depending on the route of administration.

[0041] The medicament or pharmaceutical composition of the present
invention may for example be administered parentally in combination with
conventional injectable liquid carriers, such as water or suitable
alcohols. Conventional pharmaceutical excipients for injection, such as
stabilizing agents, solubilizing agents, and buffers, may be included in
such injectable compositions. These medicaments or pharmaceutical
compositions may for example be injected intramuscularly,
intraperitoneally, or intravenously.

[0042] Medicaments or pharmaceutical compositions according to the present
invention may also be formulated into orally administrable compositions
containing one or more physiologically compatible carriers or excipients,
in solid or liquid form. These compositions may contain conventional
ingredients such as binding agents, fillers, lubricants, and acceptable
wetting agents. The compositions may take any convenient form, such as
tablets, pellets, granules, capsules, lozenges, aqueous or oily
solutions, suspensions, emulsions, or dry powdered forms suitable for
reconstitution with water or other suitable liquid medium before use, for
immediate or controlled release. The multiparticulate forms, such as
pellets or granules, may e.g. be filled into a capsule, compressed into
tablets or suspended in a suitable liquid.

[0044] Medicaments or pharmaceutical compositions according to the present
invention may also comprise an enteric coating, so that their dissolution
is dependent on pH-value. Due to said coating the medicament may pass the
stomach undissolved and the respective pharmaceutical composition and its
components is/are liberated in the intestinal tract. Preferably the
enteric coating is soluble at a pH value of 5 to 7.5. Suitable materials
and methods for the preparation are known from the prior art.

[0045] Typically, the medicaments or pharmaceutical compositions according
to the present invention may contain 1-60% by weight of the combination
of (rac)-tramadol.HCl and celecoxib as defined herein and 40-99% by
weight of one or more auxiliary substances (additives/excipients).

[0046] The compositions of the present invention may also be administered
topically or via a suppository.

[0047] The daily dosage for humans and animals may vary depending on
factors that have their basis in the respective species or other factors,
such as age, sex, weight or degree of illness and so forth. The daily
dosage for humans preferably is in the range of 10 to 2000 milligrams of
active substance to be administered during one or several intakes per
day.

[0048] A further aspect of the invention relates to a pharmaceutical
composition according to the invention comprising the combination of
(rac)-tramadol.HCl and celecoxib according to the invention for use as an
analgesic for the treatment of pain, preferably acute pain, chronic pain,
neuropathic pain, hyperalgesia, allodynia or cancer pain, including
diabetic neuropathy and osteoarthritis; as well as severe to moderate
pain; including also rheumatoid arthritis, ankylosing spondylitis,
sciatica and frozen shoulder. The use of the pharmaceutical composition
might especially be drawn to the treatment of severe to moderate pain
with an inflammatory component like e.g. rheumatoid arthritis, ankylosing
spondylitis, sciatica and frozen shoulder.

[0049] A further aspect of the invention relates to a pharmaceutical
composition according to the invention comprising the combination of
(rac)-tramadol.HCl and celecoxib according to the invention for use as an
analgesic or for the treatment of pain, preferably acute pain, chronic
pain (acute and chronic pain), neuropathic pain, nociceptive pain
(visceral and/or somatic pain), mild and severe to moderate pain,
hyperalgesia, pain related to central sensitization, allodynia or cancer
pain, including diabetic neuropathy or diabetic peripheral neuropathy and
osteoarthritis, fibromyalgia; rheumatoid arthritis, ankylosing
spondylitis, frozen shoulder or sciatica. A further aspect of the
invention relates to a pharmaceutical composition according to the
invention comprising the combination of (rac)-tramadol.HCl and celecoxib
according to the invention for the treatment of pain, preferably acute
pain, or preferably acute pain, chronic pain (acute and chronic pain),
neuropathic pain, nociceptive pain (visceral and/or somatic pain), mild
and severe to moderate pain, hyperalgesia, pain related to central
sensitization, allodynia or cancer pain, including diabetic neuropathy or
diabetic peripheral neuropathy and osteoarthritis, fibromyalgia;
rheumatoid arthritis, ankylosing spondylitis, frozen shoulder or
sciatica. The invention thus also relates to the use of a co-crystal
according to the invention as described above in the production of a
medicament for the treatment of pain, preferably acute pain, chronic pain
(acute and chronic pain), neuropathic pain, nociceptive pain (visceral
and/or somatic pain), mild and severe to moderate pain, hyperalgesia,
pain related to central sensitization, allodynia or cancer pain,
including diabetic neuropathy or diabetic peripheral neuropathy and
osteoarthritis, fibromyalgia; rheumatoid arthritis, ankylosing
spondylitis, frozen shoulder or sciatica.

[0050] A related further aspect of the invention is aimed at the use of a
pharmaceutical composition according to the invention as described above
in the manufacture of a medicament for the treatment of pain, preferably
acute pain, chronic pain, neuropathic pain, hyperalgesia, allodynia or
cancer pain, including diabetic neuropathy, fibromyalgia or
osteoarthritis; as well as severe to moderate pain; including also
rheumatoid arthritis, ankylosing spondylitis, sciatica and frozen
shoulder. Preferably this use is provided for in form of a medicament or
a pharmaceutical composition according to the invention as described
above. This medicament might especially be drawn to the treatment of
severe to moderate pain with an inflammatory component like e.g.
rheumatoid arthritis, ankylosing spondylitis, sciatica and frozen
shoulder. Another related further aspect of the invention is aimed at the
use of a pharmaceutical composition according to the invention as
described above in the manufacture of a medicament for the treatment of
pain, preferably acute pain, chronic pain (acute and chronic pain),
neuropathic pain, nociceptive pain (visceral and/or somatic pain), mild
and severe to moderate pain, hyperalgesia, pain related to central
sensitization, allodynia or cancer pain, including diabetic neuropathy or
diabetic peripheral neuropathy and osteoarthritis, fibromyalgia;
rheumatoid arthritis, ankylosing spondylitis, frozen shoulder or
sciatica.

[0051] Another object of the current invention is a method of treatment of
pain, preferably acute pain, chronic pain, neuropathic pain,
hyperalgesia, allodynia or cancer pain, including diabetic neuropathy,
fibromyalgia or osteoarthritis; as well as severe to moderate pain;
including also rheumatoid arthritis, ankylosing spondylitis, sciatica and
frozen shoulder, by providing to a patient in need thereof a sufficient
amount of the pharmaceutical composition comprising the combination of
(rac)-tramadol.HCl and celecoxib according to the invention as described
above. This method of treatment might especially be relevant for the
treatment of severe to moderate pain with an inflammatory component like
e.g. rheumatoid arthritis, ankylosing spondylitis, sciatica and frozen
shoulder. Another related object of the invention is aimed at a method of
treatment of pain, preferably acute pain, chronic pain (acute and chronic
pain), neuropathic pain, nociceptive pain (visceral and/or somatic pain),
mild and severe to moderate pain, hyperalgesia, pain related to central
sensitization, allodynia or cancer pain, including diabetic neuropathy or
diabetic peripheral neuropathy and osteoarthritis, fibromyalgia;
rheumatoid arthritis, ankylosing spondylitis, frozen shoulder or sciatica
by providing to a patient in need thereof a sufficient amount of the
pharmaceutical composition comprising the combination of
(rac)-tramadol.HCl and celecoxib according to the invention as described
above.

[0052] "Pain" is defined by the International Association for the Study of
Pain (IASP) as "an unpleasant sensory and emotional experience associated
with actual or potential tissue damage, or described in terms of such
damage (IASP, Classification of chronic pain, 2nd Edition, IASP
Press (2002), 210). Even though pain is always subjective its causes or
syndromes can be classified. One classification to denominate subtypes of
pain would be to divide the general pain syndrome into the subtypes of
acute and chronic pain or--according to the pain intensity--into mild,
moderate and severe pain. In other definitions the general pain syndrome
is also divided into "nociceptive" (caused by activation of nociceptors),
"neuropathic" (caused by damage to or malfunction of the nervous system)
and pain related to central sensitization (central pain syndrome).

[0053] "Sciatica" or "sciatic neuritis" is defined herein as a set of
symptoms including pain that derive from irritation of the sciatic nerve
or its roots,

[0054] "Frozen shoulder" or "adhesive capsulitis" is defined herein as a
symptom wherein the connective tissue surrounding the shoulder joint or
the shoulder capsule itself is causing chronic pain, becoming inflamed
and stiff.

[0055] "Ankylosing spondylitis" or "Morbus Bechterew" is a chronic,
inflammatory arthritis and autoimmune disease. It mainly affects joints
in the spine and the sacroilium in the pelvis, causing eventual fusion of
the spine.

[0056] "Pain related to central sensitization"/"central pain syndrome" is
defined within this application as a neurological condition caused by
damage to or dysfunction of the central nervous system (CNS), which
includes the brain, brainstem, and spinal cord. This syndrome can inter
alia be caused by stroke, multiple sclerosis, tumors, epilepsy, brain or
spinal cord trauma, or Parkinson's disease.

[0057] "Nociceptive pain" is defined as a type of pain caused by
activation of nociceptors. It can be divided into somatic and visceral
pain. "Visceral pain" is pain generally originating from the organs,
whereas "(deep) somatic pain" originates from ligaments, tendons, bones,
blood vessels, fasciae and muscles.

BRIEF DESCRIPTION OF THE FIGURES

[0058] FIG. 1:

[0059] A: Dose response curves of antihyperalgesic effects of tramadol,
celecoxib and different combinations of racemic tramadol hydrochloride
with celecoxib at different ratios (1:1, 1:3 and 3:1) in the rat paw
incision model of postoperative pain.

[0061] The present invention is illustrated below with the help of the
following examples. These illustrations are given solely by way of
example and do not limit the invention.

EXAMPLES

Example 1

Preparation of Composition Doses of Tramadol Hydrochloride and Celecoxib

[0062] Combinations of a racemic tramadol hydrochloride and celecoxib were
prepared at different molar ratios of (rac)-tramadol.HCl:celecoxib (1:1,
1:3 and 3:1). All drugs and combinations were dissolved in 0.5%
hydroxypropyl methylcellulose in distilled water and administered in a
volume of 10 ml/kg per rat through the intraperitoneal (i.p.) route. In
Table 1 are listed the different ratios prepared at the various
concentrations,

[0063] The aim of this study was to evaluate the analgesic efficacy and
potency of compositions comprising a combination of tramadol/celecoxib,
especially a combination of racemic tramadol hydrochloride with celecoxib
in different molar ratios (1:1, 1:3 and 3:1) in a rat model of
postoperative pain after paw incision. To assess the reliability of the
efficacy and potency of the compounds tested thermal hypersensitivity
(hyperalgesia) was performed using the plantar test assay (Hargreaves et
al., Pain 1988, 32, 77).

Experimental Design:

Animals

[0064] Male, Wistar rats (120-160 g, Harlan, Italy) were housed in a
climate-controlled room for at least 5 days prior to testing. Food and
water were available ad libitum up to test time.

Animal Dosing

[0065] The rats were all dosed intraperitoneally with compositions
comprising a combination of racemic tramadol hydrochloride and celecoxib
at different ratios, dissolved in a suspension of 0.5% hydroxypropyl
methylcellulose in distilled water. The dosing volume was 10 ml/kg. The
antihyperalgesic response of the animal was subsequently evaluated 60 min
after compositions administration.

Surgery

[0066] Rats were anaesthetized with 3% isofluorane and a 1 cm longitudinal
incision was made through skin and fascia of the plantar surface of the
paw, starting 0.5 cm from the proximal edge of the heel and extending
toward the toes. Both superficial (skin) and deep (muscle) tissues and
nerves were injured. Finally, the skin of the paw was stitched with a
suturing stitch with breaded silk (3.0).

Assessment of Analgesic Activity in Post-Operative Pain in Rats

[0067] The drugs were tested 4 hours after the surgery (plantar incision);
60 minutes after the administration of the product,

Assessment of Thermal Hypersensitivity (Hyperalgesia) in Post-Operative
Pain in Rats

[0068] Thermal hypersensitivity or hyperalgesia was assessed by
measurement of a response to a thermal stimulus using a Hargreaves
apparatus (Ugo Basile plantar test) which selectively elevates the
temperature of an individual paw (Ding, et al., J Neurosci Methods, 1997,
76, 183). Animals were placed in the methacrylate cages of said
apparatus, having a crystal floor. The acclimation period within the
cages was about 10 minutes. The thermal stimulus came from a lamp moving
below the crystal floor and which was applied to both paws, with a
minimum interval of 1 minute between both stimulations in order to avoid
learning behaviours. The rat is able to withdraw the paw freely when it
feels discomfort (pain) produced by the heat coming from the lamp; then
it is switched off and the latency time to the withdrawal response is
recorded in seconds. In order to avoid hurting the animal's paw, the lamp
was automatically switched off after 32 seconds. Hyperalgesia is defined
as an increased response to a painful stimulus and the analgesic effect
of the test compound is seen as a (partial) restoration of the latency
toward normal (Dirig, et al., J. Pharmacol Expt Therap. 1998, 285, 1031).

Analysis of Synergistic Effect

[0069] The synergistic interaction between tramadol and celecoxib was
determined by isobologram analysis as discloses by R. J. Tallarida, et
al., Life Sci., 1989, 45, 947. This procedure involves the determination
of the total amount in the mixture that is required to produce a
specified synergistic anti-hyperalgesic effect at the 50% dose level
(that is, the ED50 or Zt) and the corresponding total amount that
would be expected under simple additivity (ED50 add or Zadd). Where
it is established that Zt<Zadd for a specific fixed-ratio, then that
composition has a synergistic anti-hyperalgesic effect. Both ED50 t
and ED50 add values are random variables. ED50 t is determined
from the dose-response curve for a specific fixed-ratio of the
components; ED50 add is calculated from the ED50 values for the
individual drugs. Zt is then compared to Zadd via a Student's t-test.

Results:

[0070] In this study, dose response curves of compositions comprising a
combination of racemic tramadol hydrochloride and celecoxib at different
ratios (1:1, 1:3 and 3:1) were obtained (see FIG. 1A). All drugs induced
full efficacy when thermal hypersensitivity was evaluated.

[0071] All ratios of combination of racemic tramadol hydrochloride with
celecoxib resulted to act synergistically inhibiting thermal hyperalgesia
in postoperative pain rats. The ratios 1:1 and 3:1 improved significantly
around 4 times the antihyperalgesic effects. The ratio 1:3 improved
around 1 time the antihyperalgesic effects (see Table 2 and FIG. 1B).